Active Maintenance Improves Progression-Free Survival in mCRC

Dirk Arnold, MD

Two active maintenance regimens following disease stabilization with standard induction therapy demonstrated superior disease-free outcomes compared with no treatment in patients with metastatic colorectal cancer (mCRC), according to findings of a phase III trial (AIO KRK 0207) presented at the 2014 World Congress on Gastrointestinal Cancer held in Barcelona. Patients who received maintenance treatment with fluoropyrimidines plus bevacizumab or bevacizumab monotherapy experienced progression-free survival (PFS). Abstract O-0027

The optimal strategy for maintenance with bevacizumab following combination chemotherapy has remained unsettled. Dirk Arnold, MD, Director, Department of Medical Oncology, Tumour Biology Centre in Freiburg, Germany, and colleagues evaluated whether maintenance with no therapy or maintenance with bevacizumab monotherapy was noninferior to fluoropyrimidines plus bevacizumab following successful induction treatment

“Progression-free survival was improved with active maintenance treatment but it is too soon to tell if there is an effect on overall survival,” said Arnold.

The trial enrolled 840 patients with mCRC who received 24 weeks of induction treatment with fluoropyrimidines, oxaliplatin, and bevacizumab. After completing this treatment, 473 patients who did not experience disease progression were randomized into one of the following arms: Arm A, standard maintenance treatment with fluoropyrimidines and bevacizumab (n = 141); arm B, bevacizumab monotherapy (n = 153); or arm C, no treatment (n = 153). The initial induction therapy regimen would be readministered if any patients exhibited disease progression.

The primary endpoint of the trial was time to failure of strategy (TFS), which included the time of first induction treatment and duration of maintenance until disease progression. Secondary endpoints included time to first progression (PFS1) and overall survival (OS).

Following initial induction therapy, the response rate (RR: complete response [CR] + partial response [PR]) was 60% in arm A and B versus 59% in arm C. The best response of stable disease was reported for 40% of patients in arms A and B versus 41% of patients in arm C.

After being assigned to a maintenance strategy, patients achieved median PFS1 in arms A, B, and C of 6.2, 4.8, and 3.6 months, respectively. PFS1 from start of induction was 11.7 months, 10.2 months, and 9 months in arms A, B, and C, respectively.

TFS favored arm A over arm C (HR = 1.22; 95% CI, 0.96-1.57; P = .11), but did not reach statistical significance. A statistically significant difference was not observed between arms A and B in TFS (HR = 0.98; 95% CI, 0.76-1.28; P = .85).

Few patients terminated maintenance because of unacceptable toxicity: 8%, 5% and 1% of patients in arms A, B, and C, respectively. However 58%, 79%, and 86%, of patients in arms A, B, and C, respectively, discontinued because of disease progression.

The reinduction rate was low overall at 37%; upon first progression; only 24% of patients in arm A and 47 % of patients in arms B and C received reinduction.

Rates for grades 1, 2, and 3 toxicity during maintenance were similar across all three arms.

After 200 documented events, preliminary OS was 23.4 months from randomization, without significant difference between treatment arms (P = .69).

The researchers concluded that bevacizumab alone is noninferior to bevacizumab combined with fluoropyrimidines as maintenance, but no active maintenance is inferior to combination maintenance. In addition, immediate reinduction rates upon first progression were too low to accept this strategy.

“I suspect, but we do not know, that irinotecan toxicity was a factor in patients’ decisions to forgo reinduction therapy,” Arnold remarked.

Nurse Perspective

Laura Metcalfe, MSN, RN, APN-C, AOCNS

John Theurer Cancer Center Hackensack, NJ

Whether to continue chemotherapy or give a treatment holiday in the disease-stable mCRC patient has long been an area of concern—both to the patients and to clinicians. Historically, we have offered the patients both options. Some patients opt for the treatment break, fully understanding that when the disease becomes active again treatment will be resumed. Others opt to continue treatment citing concerns about disease progression. Traditionally this has been a discussion between the patient and the physician, looking at the pros and cons of each decision, and ultimately with the patient making the final decision.

The researchers in this study compared maintenance with no therapy (ie, “observation”) versus either maintenance with bevacizumab monotherapy or fluoropyrimidines plus bevacizumab. They concluded that bevacizumab alone is noninferior to bevacizumab combined with fluoropyrimidines as maintenance; however, no active maintenance is inferior to combination therapy.

This study may take some of the debate out of the conversation regarding what to do in the mCRC patient with disease stabilization. The only question remaining may be bevacizumab alone or plus a fluoropyrimidine. Tolerance of the therapy may be the deciding factor. In our practice, we have been offering patients capecitabine plus bevacizumab as maintenance, based on the results of the CAIRO3 trial which found that maintenance with capecitabine plus bevacizumab significantly delayed disease progression, compared to observation. Given that capecitabine is an oral therapy, many patients find this option more appealing than continuing the 46-hour intravenous fluorouracil treatment every 2 weeks. In addition, the bevacizumab can be given once every 3 weeks, leading to fewer and shorter visits to the oncology clinic.

Given that patients with mCRC are often living a long time with their disease, defining the appropriate treatment, including maintenance, remains vital. This new study has added some needed clarity to the issue.